The ongoing Selenium-vitamin E Cancer Trial (SELECT) is testing the efficacy of selenium (Se) in the form of selenomethionine (SeMet) alone or in combination with vitamin E to prevent prostate cancer (PCa) in a cohort of some 32,400 North American men. The results are expected in a decade. If a positive preventive efficacy is confirmed, the public health impact of using this form of Se is self-evident, and this will provide an outstanding impetus for further clinical trials to identify more efficacious Se agents to realize even greater preventive benefits. If negative, the quest for effective Se agents takes on significant urgency. Cell culture studies by us and others suggest that methylselenol and its immediate precursors such as methylseleninic acid (MSeA, we refer them collectively as methyl-Se) are much more efficacious than SeMet with respect to a number of anti-PCa processes such as inhibiting angiogenic switch mechanisms, inducing G1 cell cycle arrest, decreasing AKT activation and inducing caspase-mediated apoptosis. We and others have recently shown that methyl-Se inhibits androgen receptor (AR) expression and signaling, which are crucial for PCa development. Furthermore, we have now in pilot studies found that MSeA and methylselenocysteine (MSeC) given by daily oral dosing exerted dose-dependent inhibition of DU145 human PCa xenograft growth in athymic nude mice and SeMet at the same dosage did not. We hypothesize that methyl-Se prevents PCa in vivo by its broad-spectra anti-cancer actions through inhibiting tumor angiogenesis, cell cycle arrest and/or an induction of caspase-mediated apoptosis as well as by the prostate organ-specific inhibition of AR expression and signaling. To test this hypothesis, we propose 3 specific aims in both androgen-dependent (AD) and androgen-independent (AI) PCa xenograft models and the TRAMP (TRansgenic Adenocarcinoma Mouse Prostate) primary prostate carcinogenesis model. We will establish the in vivo chemopreventive efficacy of MSeA and MSeC vs. SeMet and characterize and validate key mechanistic biomarkers such as VEGF suppression for anti-angiogenesis and AR and PSA suppression for inhibition of androgen signaling. We expect to provide valuable efficacy and biomarker data to guide the design of future clinical translational studies with methyl-Se with greater prostate specific targeting actions. They will also be insightful for predicting and interpreting the outcomes of the SELECT study. [unreadable] Narrative: The results from these studies will provide valuable in vivo efficacy and biomarker data to guide the design of future human clinical trials for methyl selenium for prostate cancer chemoprevention. They will also be instructive for predicting and interpreting the outcomes of the ongoing selenium cancer prevention trials. [unreadable] [unreadable] [unreadable] [unreadable]